Systemic sclerosis (SSc) affects approximately 200,000 individuals in the USA alone. Treatment for SSc is difficult, incomplete, and not curative. Th2-cytokine polarized T cell responses are postulated to mediate inflammation, auto-antibody production and development of fibrosis in SSc, yet there remains a wide knowledge gap on specific molecules involved in the Th2 cytokine-driven immunopathology of SSc. Interleukin- 31 (IL-31) is a newly identified cytokine produced by activated Th2 T cells and overproduction of IL-31 in mouse skin has been shown to cause severe pruritus, alopecia and skin lesions similar to those seen in SSc. IL-31 signals exclusively through a heterodimeric receptor complex consisting of IL-31 receptor alpha (IL-31RA) and oncostatin M receptor beta (OSMR). Preliminary data from our laboratory show elevated expression of IL-31, IL-31RA and OSMR in skin lesions of bleomycin-induced SSc. In addition, key Th-2 cytokines IL-4 and IL-13 directly increased IL-31RA expression in inflamed macrophages. These findings support our central hypothesis that Th2 cytokines and IL-31-IL-31RA interactions play an essential role in the immunopathology of SSc. The objective of this application is to identify the in vivo regulation of the IL-31RA subunit expression by IL-4 and IL-13 and the role of IL-31 in the immunopathology of SSc. Our long-term goal is to understand how the Th2 cytokines and IL-31-IL-31RA interactions can be manipulated for preventive and therapeutic purposes in SSc. This hypothesis will be tested by pursuing two specific aims: 1) Determine the molecular regulation of IL-31RA expression by IL-4 and IL-13 using a mouse model of bleomycin-induced SSc; and 2) Identify the role of IL-31-IL-31RA interactions in the immunopathology of SSc. Under the first aim, we will test the hypothesis that the Th2 cytokines, IL-4 and IL-13 regulate IL-31RA expression in skin cells in a mouse model of bleomycin-induced SSc. This aim will establish the cells and Th2 cytokine signaling pathways involved in IL-31 and IL-31RA expression. The second aim will compare wild type and IL-31RA deficient mice for the evolution of disease phenotypes including inflammation, auto-antibody production and fibrosis in the skin during bleomycin-induced SSc. This aim will provide proof of concept for the potential therapeutic benefit of inhibiting IL-31-IL-31RA interactions in SSc. The approach is innovative by testing molecular interactions among IL-4, IL-13 and IL-31 and their pathologic skin responses using a mouse model of bleomycin-induced SSc and knock-out mice. The proposed research is significant, because completion of this study will increase our knowledge of the mechanisms causing SSc and will lead to better medical treatments, cure or prevention.